FOXP3 and GARP (LRRC32): the master and its minion

The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (Treg) cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32) recently identified as specific marker of activated human Treg cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype

Hierarchical structure and modules in the Escherichia coli transcriptional regulatory network revealed by a new top-down approach

BACKGROUND: Cellular functions are coordinately carried out by groups of genes forming functional modules. Identifying such modules in the transcriptional regulatory network (TRN) of organisms is important for understanding the structure and function of these fundamental cellular networks and essential for the emerging modular biology. So far, the global connectivity structure of TRN has not been well studied and consequently not applied for the identification of functional modules. Moreover, network motifs such as feed forward loop are recently proposed to be basic building blocks of TRN. However, their relationship to functional modules is not clear. RESULTS: In this work we proposed a top-down approach to identify modules in the TRN of E. coli. By studying the global connectivity structure of the regulatory network, we first revealed a five-layer hierarchical structure in which all the regulatory relationships are downward. Based on this regulatory hierarchy, we developed a new method to decompose the regulatory network into functional modules and to identify global regulators governing multiple modules. As a result, 10 global regulators and 39 modules were identified and shown to have well defined functions. We then investigated the distribution and composition of the two basic network motifs (feed forward loop and bi-fan motif) in the hierarchical structure of TRN. We found that most of these network motifs include global regulators, indicating that these motifs are not basic building blocks of modules since modules should not contain global regulators. CONCLUSION: The transcriptional regulatory network of E. coli possesses a multi-layer hierarchical modular structure without feedback regulation at transcription level. This hierarchical structure builds the basis for a new and simple decomposition method which is suitable for the identification of functional modules and global regulators in the transcriptional regulatory network of E. coli. Analysis of the distribution of feed forward loops and bi-fan motifs in the hierarchical structure suggests that these network motifs are not elementary building blocks of functional modules in the transcriptional regulatory network of E. coli

Dynamic cumulative activity of transcription factors as a mechanism of quantitative gene regulation

By combining information on the yeast transcription network and high-resolution time-series data with a series of factors, support is provided for the concept that dynamic cumulative regulation is a major principle of quantitative transcriptional control

Sustainability challenges and how Industry 4.0 technologies can address them: a case study of a shipbuilding supply chain

The shipbuilding industry is under significant economic pressure and in need of more efficient solutions to secure economically sustainable operations. It is also challenged by social issues and the need for a greener maritime industry is critical. Accordingly, the shipbuilding industry is pressured across all three dimensions of sustainability. This paper aims to identify the sustainability challenges in shipbuilding supply chains and explore how Industry 4.0 technologies can impact the sustainability of shipbuilding. This is achieved through a case study of a shipbuilding supply chain, which results in the identification of its primary sustainability challenges. Further, this work proposes a set of nine digital solutions to support sustainable operations in shipbuilding as the paper’s primary contribution. This lays the foundation for further empirical research on sustainability and digitalization in shipbuilding, while for practice the paper provides enhanced insight into how Industry 4.0 technologies can be adopted in shipbuilding supply chains.acceptedVersio

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4+ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4+ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4+ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation

The potential of nanoparticles for the immunization against viral infections

Vaccination has a great impact on the prevention and control of infectious diseases. However, there are still many infectious diseases for which an effective vaccine is missing. Thirty years after the discovery of the AIDS-pathogen (human immunodeficiency virus, HIV) and intensive research, there is still no protective immunity against the HIV infection. Over the past decade, nanoparticulate systems such as virus-like particles, liposomes, polymers and inorganic nanoparticles have received attention as potential delivery vehicles which can be loaded or functionalized with active biomolecules (antigens and adjuvants). Here we compare the properties of different nanoparticulate systems and assess their potential for the development of new vaccines against a range of viral infections

Depletion of Foxp3(+) regulatory T cells is accompanied by an increase in the relative abundance of Firmicutes in the murine gut microbiome

A reciprocal interaction exists between the gut microbiota and the immune system. Regulatory T (Treg) cells are important for controlling immune responses and for maintaining the intestinal homeostasis but their precise influence on the gut microbiota is unclear. We studied the effects of Treg cell depletion on inflammation of the intestinal mucosa and analysed the gut microbiota before and after depletion of Treg cells using the DEpletion of REGulatory T cells (DEREG) mouse model. DNA was extracted from stool samples of DEREG mice and wild‐type littermates at different time‐points before and after diphtheria toxin application to deplete Treg cells in DEREG mice. The V3/V4 region of the 16S rRNA gene was used for studying the gut microbiota with Illumina MiSeq paired ends sequencing. Multidimensional scaling separated the majority of gut microbiota samples from late time‐points after Treg cell depletion in DEREG mice from samples of early time‐points before Treg cell depletion in these mice and from gut microbiota samples of wild‐type mice. Treg cell depletion in DEREG mice was accompanied by an increase in the relative abundance of the phylum Firmicutes and by intestinal inflammation in DEREG mice 20 days after Treg cell depletion, indicating that Treg cells influence the gut microbiota composition. In addition, the variables cage, breeding and experiment number were associated with differences in the gut microbiota composition and these variables should be respected in murine studies

Gene expression signatures of peripheral CD4+ T cells clearly discriminate between patients with acute and chronic hepatitis B infection

CD4+ T and regulatory T cells (Tregs) seem to play a key role in persistence of hepatitis B virus (HBV) infection. However, the molecular events by which Tregs exert their modulatory activity are largely unknown. The transcriptional profiles of CD4+ T cells of healthy controls (HCs) and patients affected by acute hepatitis B (AVH-B) or chronic hepatitis B (CHB) infection were established using a custom expression array consisting of 350 genes relevant for CD4+ T cell and Treg function. These studies were complemented by real-time reverse-transcription polymerase chain reaction. Peripheral blood mononuclear cells (PBMCs) were also analyzed for the presence of Tregs, which were more abundant in the acute stage of the disease (7%) than in HCs and CHB infection (HCs versus AVH-B, P = 0.003; AVH-B versus CHB, P = 0.04). One hundred eighteen genes (34%) intrinsically differentiate HBV-infected patients from HCs. Using gene ontology, we identified T cell receptor signaling and clusterization, mitogen-activated protein kinase kinase signaling, cell adhesion, cytokines and inflammatory responses, cell cycle/cell proliferation, and apoptosis as the most prominent affected modules. A higher expression of CCR1, CCR3, CCR4, CCR5, and CCR8 was seen in AVH-B than in CHB-infected patients and HCs. Annotation of the interconnected functional network of genes provided a unique representation of global immune activation during acute infection. Almost all genes were down-regulated in patients with CHB infection. Conclusion: The fingerprints enable clear discrimination between patients suffering from AVH-B or CHB infection. The observed profiles suggest accumulation of effector T cells with a potential role in necro-inflammation during the acute stage. Subsequent down-regulated effector functions support the hypothesis of suppressed CD4+ effector T cells favoring viral persistence in the chronic infection stage